Gene Therapy Extends Lifespan and Reverses Age-Related Changes in Normal Aged Mice

“In this study, we show that systemically delivered adeno-associated viruses, encoding an inducible OSK system, in 124-week-old male mice extend the median remaining lifespan by 109% over WT controls and enhance several health parameters.”

Press Release:

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Macip CC, Hasan R, Hoznek V, Kim J, Lu YR, Metzger LE 4th, Sethna S, Davidsohn N. Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice. Cell Reprogram. 2024 Feb;26(1):24-32. doi: 10.1089/cell.2023.0072. PMID: 38381405.

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Its a start… but 9% improvement isn’t much (about what the ITP found with Glycine I think), and well below rapamycin.

I hope this is just the start of progress in this area and that they get much better results in the future.

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It was a 109% increase in median remaining lifespan, not a 9% increase. The mice were already old at the time the treatment started, equivalent to about 80 years of age in humans.

Doxycycline was also tested. It had no effect on remaining lifespan when compared to published historical control data.

This is a really confusing and deceptive metric that isn’t typically used in longevity studies. Richard Miller has commented on measurements like this… they are very deceiving and pretty much useless. You could give a treatment to a couple of mice that are in the last week of their life and if you extend their lifespan by a month you’ve quadrupled (400%!) their median life expectancy. Amazing!.. But not really.

So, I say this is a BS metric, more for marketing than anything else.

I don’t have the time right now - but it would be interesting to translate that into the typical measures as seen in the ITP studies. The full (pre-peer review) paper is here: https://www.biorxiv.org/content/10.1101/2023.01.04.522507v2.full

The only other study I’m aware of that has measured the lifespan improvement as a function of the “Remaining” lifespan (vs. median total lifespan of controls) is the “transient rapamycin trial” done by Allesandro Bitto of Kaeberlein’s lab where they got a “60% improvement in median remaining lifespan”, but nobody goes around saying that rapamycin gives you a 60% increase in lifespan because we all know thats a bogus measure.

Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice.

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In my view this is very exciting, but early. The potential of partial reprogramming - if made to a safe therapy for humans could be truly massive. And it could potentially be done several times during a human’s lifespans.

Rapa, Acar, SGLTi, etc can hopefully get us to a future where partial reprogramming, meaningful CRISPR and replacement therapies could give us many extra decades of healthy, amazing life.

This is a good summary of how I feel about it the study:

These observations, along with recent advances in vector development and optimization, tissue-specific promoters, and inducible systems (Domenger and Grimm, 2019; Li and Samulski, 2020), engender cautious optimism that a partial rejuvenation therapy can be safely delivered in humans.

Because this

A.

To our knowledge, we have shown for the first time an extension of remaining median lifespan in extremely old WT C57BL6/J mice concomitantly with improved health outcomes as a consequence of a systemic AAV-based partial reprogramming therapy.

and

B.

We did not notice any gross teratoma formation when we processed the tissues from animals receiving AAV9-EF1a-rtTA4 ; TRE-OSK or AAV9-CMV-OSK , or during the frailty score measurement

And I like their ambitious, audacious attitude:

Based on our novel proof-of-concept studies in an extremely aged mouse population (equivalent to >80 years of age in humans) and previous studies in younger mice (Browder et al., 2022; Lu et al., 2020; Ocampo et al., 2016), we envision therapeutic rejuvenation in aged humans, first in a specific age-related disease setting and later for therapeutic healthspan and lifespan extension.

Here are the numbers if anyone wants to do the math @RapAdmin suggested - just note that since they started so very late in life, one cannot really compare to ITP type of studies. That would not be apples to apples (either) since the ITP mice even in their subset of “late life”studies were treated much earlier/longer than in the OSK study here

(to compare with rapa/acar, etc, one would have to either do a new rapa/acar, etc study extremely late in life of the mice - or do the partial reprogramming study with start earlier in life (and then perhaps give additional subsequent cycles during the mice’s lives).

control mice had a median lifespan of ∼133 weeks, whereas the TRE-OSK mice had a median lifespan of 142.5 weeks (Fig. 1b, c and Supplementary Fig. S1): a remarkable 109% extension in median remaining life in response to OSK expression (control mice had 8.86 weeks of life remaining vs. 18.5 weeks for TRE-OSK mice).

Graphically here is the key the data

IMG_6880
IMG_6881

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I completely agree. The area shows great potential and I hope progress in the area continues, with more lifespan studies on middle aged mice.

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Support for the study being exciting (Sinclair has pinned it as it opening and standing tweet
) and a thread from the company:


https://twitter.com/cellrepjrnl/status/1760717209297670307?s=46&t=zJMJ1xVdRJYEDYz-DHipTw

Source: https://x.com/AlexJColville/status/1761933967106662849?s=20

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Do we have any rapa study (or any ITP or even non ITP longevity study of other compounds) where rapa (or other compound) is given as late in life (around week 125 / human equivalent ~80 years) as in this reprogramming study?

While as mentioned above I agree that the “doubling” of remaining of life that late in life from the reprogramming paper is not a established metric…

… is also not fair to compare lifelong or since middle age/half of the life’s duration continuous/long-term treatment with rapa (or other compound) to just one single limited treatment window at the almost end of life as in the partial reprogramming study

So Dr Lamming’s comparison below is equally bad / not at all apples to apples:

IMG_6917

No, but I would still argue you need to stick to the standard way of measuring lifespan extension so that results are comparable. Plus, its not like you’re going to do reprogramming every day or every week (so a reprogramming study is never going to be exactly comparable to a daily-dosed small molecule drug study)…

The Mouse/Rapamycin studies: List of all the Mouse Studies Showing Rapamycin Lifespan Extension

A maximum start date of around 80 weeks.

Thx for sharing. I agree that it would be great to see what happens with partial reprogramming at earlier ages.

In any case, they did the study as they did it - we can and should criticize and put its shortcomings in context.

AND someone as steeped in science as Dr Lamming should not use retorical misleading comparisons that he knows is not an apples to apples comparison.

Just because there was one bad does not mean that people should fight the bad with other badness.

Btw - given that one of the main theoretical risks with reprogramming is potential cancer and at the same time the benefits of reprogramming might be larger the older a person is - it might be that the company actually is thinking that the first use cases in humans (which the FDA might actually be more favorable to) will be in older people.

Probably not 80 year olds as the equivalents of the mice in the study at hand, but they may seek an approvals and clinical trial path in older people.

For such therapies/use cases the study at hand might actually have been designed in a good way.

Partial cellular reprogramming: A deep dive into an emerging rejuvenation technology

Patrick T. Paine, Ada Nguyen, Alejandro Ocampo

First published: 01 December 2023

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.14039

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